Synthego’s newest offering applies genome engineering in order to address a longtime challenge in research and drug development—the dearth of high-quality, physiologically relevant biological models needed for translational medicine.

The provider of genome engineering products and services this week launched a genome engineering service for induced pluripotent stem (iPS) cells—an expansion of automated cell editing capabilities that according to Synthego is designed to achieve extremely high editing efficiency of iPS cells at an industrial scale.

Synthego reasons that iPS cells can provide one of the most reliable and accurate models for disease because they allow researchers to create patient-specific variations. Yet iPS cells created through the reprogramming of human adult cells have traditionally been difficult to handle and modify genetically.

Synthego’s new offering of iPS cells includes modification by removal of gene function (knockout), single nucleotide variation, protein tagging and other knock-ins, all with the goal of enabling scientists to generate edits at a massive scale to accelerate research and disease modeling.

“What this really enables is for a scientist to come to our website, basically describe what are the variants that they’re looking to do, tell us a little bit about the cell line, swipe their credit card, and a couple of months later, we’ll send them the genomically modified disease model, guaranteed,” Synthego CEO and co-founder Paul Dabrowski told GEN. “They get to skip the whole hassle of the learning curve, the optimization, and they get to skip the risk of failure, which is actually quite high with these types of cells.”

The guarantee, Dabrowski said, comes from the company’s extensive experience, having carried out more than 100,000 different edits in human cells. As for the timeframe for receiving cells, much of that relates to the time needed for those cells to grow in the quantities needed by researchers. Synthego is working with standard amounts for its cells, such as one million cells per vial.

Models for disorders

By using its cells, Synthego said, researchers gain access to creating models for thousands of disorders ranging from inherited conditions such as cystic fibrosis, to neurodegenerative diseases such as Alzheimer’s, and even organ-specific ocular diseases.

“Opsis is thrilled to be working with Sythego’s industry-leading platform for gene editing to help us advance our therapeutic pipeline to treat ocular diseases,” Carter Cliff, PhD, co-founder of Opsis Therapeutics, a Cellular Dynamics International company, said in a statement. Opsis is developing a pipeline of first-in-class cell replacement therapies designed to target Age Related Macular Degeneration (AMD) and inherited retinal diseases including Retinitis Pigmentosa (RP).

Dabrowski said Synthego has customers that are working on a variety of different disorders, including sickle cell disease, beta thalassemia, cystic fibrosis, and Tay Sachs disease.

“There isn’t a limitation to any particular disorder, because we have the technology to do a variety of different types of patient samples, and a variety of different types of edits,” Dabrowski said.

While there are tens of thousands of disorders that are known to scientists, he noted, the genetic basis and contribution to those disorders is not always known: “In the case of many thousands of disorders, modeling the underlying single nucleotide variations that are thought to contribute to them allows researchers to essentially validate the GWAS (genome-wide association studies) that have been going on,” Dabrowski said.

Pricing for cells will hinge on how many and what types are used, and whether the customer wants to customize cells versus ordering a standard cell line. Customers who send Synthego their own cells for customization pay more, reflecting extra time and work needed to run optimization protocols and verify that the company’s computer models are accurate for that cell type.

Mutation panels to study ADRD

Synthego’s genome-edited iPS cells will be used by the NIH’s National Institute on Aging (NIA) to create panels of mutations in a variety of genetic backgrounds to study Alzheimer’s disease and related dementias (ADRD), under a contract awarded by the agency.

The genome-edited iPS cells will introduce mutations relating to ADRD, then be characterized functionally by NIA researchers. The cells will help the NIA create a set of neurodegenerative disease models in order to better understand the disorders, and identify new ways to treat them.

“There is an intention of creating these types of models as standards that the whole research community can use. We want to enable that and open that up to all scientists, and not just those specializing in neurodegenerative disorders, or specifically Alzheimer’s. We think that’s important,” Dabrowski said.

Synthego says it is able to carry out its stem cell work through an extension of its automated cell editing platform’s capabilities focused on the editing and handling of cells, ensuring that their pluripotentcy is maintained, as well as scaling the platform so that it can do hundreds and into thousands of different disease models at the same time.

Synthego’s proprietary cell editing platform removes the difficulty of editing, cloning, and maintaining high pluripotency in clinically-relevant iPS cells, with editing rates as high as 90% prior to cloning and 100% in clones.

Using Synthego’s platform allows researchers to access the bioinformatics and predictive algorithms needed to understand how to design, and modify, the cells.

“Oftentimes, a customer won’t necessarily know how to do that,” Dabrowski said. “Even if they do, they don’t have access to these predictive algorithms, so they’ll have to do multiple rounds of CRISPR Cas-9 editing before they successfully are able to generate one of these models, if at all. They get to skip all that kind-of trial-and-error, and optimization, and kind-of go straight to the end goal by using our platform.”

“Long overdue”

“Synthego is enabling a long-overdue shift in the way models of diseases are generated through the development of optimized methods for gene editing pluripotent stem cells at scale,” said Bill Skarnes, PhD, professor and director of cellular engineering at the Jackson Laboratory.

Skarnes is a stem cell research pioneer who has joined Synthego as a member of its advisory board, after working with the company for an extended time. He was first to use gene-trapping technology in mouse embryonic stem cells in the early 1990s, then led efforts establishing a high-throughput pipeline for the production of mouse models across key research programs.

This past summer, Skarnes was corresponding author for a study detailing the development of an improved protocol for efficient engineering of single nucleotide variants in human iPS cells. The protocol, which applied CRISPR technology for “scarless” editing of single nucleotide variants, showed human iPS cells to provide an ideal model cell, Skarnes and colleagues concluded in “Improving homology-directed repair efficiency in human stem cells,” published in the July 15–August 1 issue of Methods.

Dabrowski said the new genome editing service for iPS is an example of the product and platform expansions Synthego envisioned in October 2018 when it completed its $110 million Series C financing led by Founders Fund. That financing brought the company’s total capital raised to $158 million—ranking Synthego No. 4 among private companies in GEN’s A-List of Top 10 Companies Leveraging Gene Editing in 2019, published August 12.

Since then, Redwood City, CA-based Synthego has doubled the size of its staff to about 260—but has no plans to go public.

“I think being private allows us to stay very lean and focus on developing our technologies, and not be too swayed by market trends,” Dabrowski said. “Instead, we’re going to keep developing the platform that we think is best for helping make these tools, and ultimately the medicines, successful.”

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